Federal Practitioner

I do not usually have difficulty writing editorials. However, this month was different. I kept coming up with grand ideas that flopped. First, I thought I would write a column entitled, “For What Should We Hope For?” When I started exploring the concept of hope, I quickly learned that there was extensive literature from multiple disciplines and even several centers and research projects dedicated to studying it.¹ It seemed unlikely that I would have anything worthwhile to add to that literature. Then I thought I would discuss new year’s resolutions for federal practitioners. There was not much written about that topic, yet it seemed to be overly self-indulgent and superficial to discuss eating less and exercising more amid a pandemic and a climate change crisis. Finally, I wanted to opine on the futility of telling people to be resilient when we are all exhausted and demoralized, and yet that seemed too ponderous and paradoxical for our beleaguered state. With the third strike, I finally realized I was trying too hard. And perhaps that was exactly what I needed to say, at least to myself, and maybe some readers would benefit from reading that simple message as well.

I was surprised—though I probably should not have been given the explosion of media—to find that Americans were surveyed about what months they hate most. A 2021 poll of more than 15,000 adults found that January was the most disliked month.² It’s not hard to figure out why. Characterized by a postholiday let down, these months in the middle of winter marked by either too much precipitation or if you live in the West not enough; short days and gray nights that are dark and cold. It is a long time to wait before spring with few holidays to break up the quotidian routine of work and school. January is a hard enough month in a good or even ordinary year. And 2022 is shaping up to be neither. We are entering the third year of a prolonged pandemic. Every time we have hope we are coming to the end of this long ordeal or at least things are moving toward normality, a new variant emerges, and we are back to living in fear and uncertainty.

COVID-19 is only the most relentless and deadly of our current disasters: There are rumors of wars, tornadoes, droughts, floods, shootings in schools and churches, political turmoil, and police violence. American society and the very planet seem to be in a perilous situation more than ever. No wonder then, that in the last month, several people have asked me, “Do you think this is the end of the world?” I suppose they think I am so old that I have become wise. And though I should cite a brilliant philosopher or renowned theologian: I am going to revert to my youth as a rock musician and quote R.E.M.: “It is the end of the world as we know it.” And “most of us do not feel fine!”

The world of 2022 is far more constricted and confined than it was before we heard the word COVID-19. We have less freedom of movement and fewer opportunities for companionship and gathering, for advancement and enjoyment. To thrive, and even to survive, in this cramped existence of limited possibilities, we need different values and attitudes than those that made us happy and successful in the open, hurried world before 2019. No generation since World War II has confronted such shortages of automobiles, paper goods, food, and even medicines as we have.

That is the first of the important simple messages I want to convey. Find something to be grateful for: your loved ones, your companion animals, your friends. Cherish the rainy or sunny day depending on how your climate has changed. Treasure the most basic and enduring pleasures, homemade cookies, favorite music, talking to a good friend even virtually, reading an actual book on a Sunday afternoon. These are things even the pandemic cannot take away from us unless we let our own inability to accept the conditions of our time ruin even what the meager, harsh Master of History has spared us.

The second of these simple messages is even more essential to finding any peace or joy in our current tense and somber existence: to show compassion for others and kindness to yourself. The most consistent report I have heard from people all over the country is that their fellow citizens are angry and selfish. We all understand, and even in some measure empathize with this the frustration and impatience with all the extraordinary pressure of having to function under these challenging conditions. Though we can take it out on the stranger at the grocery store or the family of the patient who has different views of masks and vaccines; it likely will not make the line shorter, the family any less demanding or seemingly unreasonable and probably will waste the little energy we have left to get home with the groceries or take care of the patient.

You never know what burden the person annoying you is carrying; it may perhaps be heavier than yours. And how we react to each other makes the weight of world weariness we all bear either easier or harder to shoulder. It sounds trite and trivial to say, yet tell people you care, and value, and love them. Although no less than Pope Francis in a Christmas present to marriages under strain from the stress of the pandemic that the 3 key words to remember are please, sorry, and thank you.³ I am applying that sage advice liberally to all relationships and interactions in the daily grind of work and home. The cost is little, the reward priceless.

It is good and right to have high hopes. We all need to take care of ourselves, whether we make resolutions to do so or not. Though more than anything else what we need is to be kind to ourselves. It is presumptuous of me to tell you what wellness means for your individual struggle, as it is inhuman of me to deign to tell you to be resilient when many of you face intolerable working conditions.⁴ As Jackson Browne sang in “Rock Me on the Water”, “Everyone must have some thought that’s going to pull them through somehow. Find your own thought, the reason you keep getting up and going to care for patients who increasingly respond with the rage of denial and resentment. Amid what morally distressed public health professionals have called so many unnecessary deaths,choose what gives you reason to keep serving that other side of this life full of healing.⁵ And if like so many of my fellow health care professionals, you are so spent and bent, that you feel that you can no longer practice without becoming someone you do not want to be, then let go with grace, get the help you deserve and perhaps one day when rested and mended, find another way to give.⁶

I rarely self-disclose but I want to end this column with a personal story that exemplifies more than all these words living this simple message. My spouse is a health care practitioner at a Veterans Affairs medical center. Like all of you on the front lines they work far too long hours in difficult conditions, with challenging patients and not enough staff to care for them. My partner had not an hour to get any gifts for me or our furry children. On Christmas Eve, before a long shift, they went to a packed Walgreens to buy our huskies each a toy and me a pair of fuzzy slippers. We sat by the tree and opened the hastily wrapped packages, and nothing could have been more memorable or meaningful. All of us at Federal Practitioner wish you, our readers, find in 2022 many such moments to sustain you.

I do not usually have difficulty writing editorials. However, this month was different. I kept coming up with grand ideas that flopped. First, I thought I would write a column entitled, “For What Should We Hope For?” When I started exploring the concept of hope, I quickly learned that there was extensive literature from multiple disciplines and even several centers and research projects dedicated to studying it.¹ It seemed unlikely that I would have anything worthwhile to add to that literature. Then I thought I would discuss new year’s resolutions for federal practitioners. There was not much written about that topic, yet it seemed to be overly self-indulgent and superficial to discuss eating less and exercising more amid a pandemic and a climate change crisis. Finally, I wanted to opine on the futility of telling people to be resilient when we are all exhausted and demoralized, and yet that seemed too ponderous and paradoxical for our beleaguered state. With the third strike, I finally realized I was trying too hard. And perhaps that was exactly what I needed to say, at least to myself, and maybe some readers would benefit from reading that simple message as well.

I was surprised—though I probably should not have been given the explosion of media—to find that Americans were surveyed about what months they hate most. A 2021 poll of more than 15,000 adults found that January was the most disliked month.² It’s not hard to figure out why. Characterized by a postholiday let down, these months in the middle of winter marked by either too much precipitation or if you live in the West not enough; short days and gray nights that are dark and cold. It is a long time to wait before spring with few holidays to break up the quotidian routine of work and school. January is a hard enough month in a good or even ordinary year. And 2022 is shaping up to be neither. We are entering the third year of a prolonged pandemic. Every time we have hope we are coming to the end of this long ordeal or at least things are moving toward normality, a new variant emerges, and we are back to living in fear and uncertainty.

COVID-19 is only the most relentless and deadly of our current disasters: There are rumors of wars, tornadoes, droughts, floods, shootings in schools and churches, political turmoil, and police violence. American society and the very planet seem to be in a perilous situation more than ever. No wonder then, that in the last month, several people have asked me, “Do you think this is the end of the world?” I suppose they think I am so old that I have become wise. And though I should cite a brilliant philosopher or renowned theologian: I am going to revert to my youth as a rock musician and quote R.E.M.: “It is the end of the world as we know it.” And “most of us do not feel fine!”

The world of 2022 is far more constricted and confined than it was before we heard the word COVID-19. We have less freedom of movement and fewer opportunities for companionship and gathering, for advancement and enjoyment. To thrive, and even to survive, in this cramped existence of limited possibilities, we need different values and attitudes than those that made us happy and successful in the open, hurried world before 2019. No generation since World War II has confronted such shortages of automobiles, paper goods, food, and even medicines as we have.

That is the first of the important simple messages I want to convey. Find something to be grateful for: your loved ones, your companion animals, your friends. Cherish the rainy or sunny day depending on how your climate has changed. Treasure the most basic and enduring pleasures, homemade cookies, favorite music, talking to a good friend even virtually, reading an actual book on a Sunday afternoon. These are things even the pandemic cannot take away from us unless we let our own inability to accept the conditions of our time ruin even what the meager, harsh Master of History has spared us.

The second of these simple messages is even more essential to finding any peace or joy in our current tense and somber existence: to show compassion for others and kindness to yourself. The most consistent report I have heard from people all over the country is that their fellow citizens are angry and selfish. We all understand, and even in some measure empathize with this the frustration and impatience with all the extraordinary pressure of having to function under these challenging conditions. Though we can take it out on the stranger at the grocery store or the family of the patient who has different views of masks and vaccines; it likely will not make the line shorter, the family any less demanding or seemingly unreasonable and probably will waste the little energy we have left to get home with the groceries or take care of the patient.

You never know what burden the person annoying you is carrying; it may perhaps be heavier than yours. And how we react to each other makes the weight of world weariness we all bear either easier or harder to shoulder. It sounds trite and trivial to say, yet tell people you care, and value, and love them. Although no less than Pope Francis in a Christmas present to marriages under strain from the stress of the pandemic that the 3 key words to remember are please, sorry, and thank you.³ I am applying that sage advice liberally to all relationships and interactions in the daily grind of work and home. The cost is little, the reward priceless.

It is good and right to have high hopes. We all need to take care of ourselves, whether we make resolutions to do so or not. Though more than anything else what we need is to be kind to ourselves. It is presumptuous of me to tell you what wellness means for your individual struggle, as it is inhuman of me to deign to tell you to be resilient when many of you face intolerable working conditions.⁴ As Jackson Browne sang in “Rock Me on the Water”, “Everyone must have some thought that’s going to pull them through somehow. Find your own thought, the reason you keep getting up and going to care for patients who increasingly respond with the rage of denial and resentment. Amid what morally distressed public health professionals have called so many unnecessary deaths,choose what gives you reason to keep serving that other side of this life full of healing.⁵ And if like so many of my fellow health care professionals, you are so spent and bent, that you feel that you can no longer practice without becoming someone you do not want to be, then let go with grace, get the help you deserve and perhaps one day when rested and mended, find another way to give.⁶

I rarely self-disclose but I want to end this column with a personal story that exemplifies more than all these words living this simple message. My spouse is a health care practitioner at a Veterans Affairs medical center. Like all of you on the front lines they work far too long hours in difficult conditions, with challenging patients and not enough staff to care for them. My partner had not an hour to get any gifts for me or our furry children. On Christmas Eve, before a long shift, they went to a packed Walgreens to buy our huskies each a toy and me a pair of fuzzy slippers. We sat by the tree and opened the hastily wrapped packages, and nothing could have been more memorable or meaningful. All of us at Federal Practitioner wish you, our readers, find in 2022 many such moments to sustain you.

I do not usually have difficulty writing editorials. However, this month was different. I kept coming up with grand ideas that flopped. First, I thought I would write a column entitled, “For What Should We Hope For?” When I started exploring the concept of hope, I quickly learned that there was extensive literature from multiple disciplines and even several centers and research projects dedicated to studying it.¹ It seemed unlikely that I would have anything worthwhile to add to that literature. Then I thought I would discuss new year’s resolutions for federal practitioners. There was not much written about that topic, yet it seemed to be overly self-indulgent and superficial to discuss eating less and exercising more amid a pandemic and a climate change crisis. Finally, I wanted to opine on the futility of telling people to be resilient when we are all exhausted and demoralized, and yet that seemed too ponderous and paradoxical for our beleaguered state. With the third strike, I finally realized I was trying too hard. And perhaps that was exactly what I needed to say, at least to myself, and maybe some readers would benefit from reading that simple message as well.

I was surprised—though I probably should not have been given the explosion of media—to find that Americans were surveyed about what months they hate most. A 2021 poll of more than 15,000 adults found that January was the most disliked month.² It’s not hard to figure out why. Characterized by a postholiday let down, these months in the middle of winter marked by either too much precipitation or if you live in the West not enough; short days and gray nights that are dark and cold. It is a long time to wait before spring with few holidays to break up the quotidian routine of work and school. January is a hard enough month in a good or even ordinary year. And 2022 is shaping up to be neither. We are entering the third year of a prolonged pandemic. Every time we have hope we are coming to the end of this long ordeal or at least things are moving toward normality, a new variant emerges, and we are back to living in fear and uncertainty.

COVID-19 is only the most relentless and deadly of our current disasters: There are rumors of wars, tornadoes, droughts, floods, shootings in schools and churches, political turmoil, and police violence. American society and the very planet seem to be in a perilous situation more than ever. No wonder then, that in the last month, several people have asked me, “Do you think this is the end of the world?” I suppose they think I am so old that I have become wise. And though I should cite a brilliant philosopher or renowned theologian: I am going to revert to my youth as a rock musician and quote R.E.M.: “It is the end of the world as we know it.” And “most of us do not feel fine!”

The world of 2022 is far more constricted and confined than it was before we heard the word COVID-19. We have less freedom of movement and fewer opportunities for companionship and gathering, for advancement and enjoyment. To thrive, and even to survive, in this cramped existence of limited possibilities, we need different values and attitudes than those that made us happy and successful in the open, hurried world before 2019. No generation since World War II has confronted such shortages of automobiles, paper goods, food, and even medicines as we have.

That is the first of the important simple messages I want to convey. Find something to be grateful for: your loved ones, your companion animals, your friends. Cherish the rainy or sunny day depending on how your climate has changed. Treasure the most basic and enduring pleasures, homemade cookies, favorite music, talking to a good friend even virtually, reading an actual book on a Sunday afternoon. These are things even the pandemic cannot take away from us unless we let our own inability to accept the conditions of our time ruin even what the meager, harsh Master of History has spared us.

The second of these simple messages is even more essential to finding any peace or joy in our current tense and somber existence: to show compassion for others and kindness to yourself. The most consistent report I have heard from people all over the country is that their fellow citizens are angry and selfish. We all understand, and even in some measure empathize with this the frustration and impatience with all the extraordinary pressure of having to function under these challenging conditions. Though we can take it out on the stranger at the grocery store or the family of the patient who has different views of masks and vaccines; it likely will not make the line shorter, the family any less demanding or seemingly unreasonable and probably will waste the little energy we have left to get home with the groceries or take care of the patient.

You never know what burden the person annoying you is carrying; it may perhaps be heavier than yours. And how we react to each other makes the weight of world weariness we all bear either easier or harder to shoulder. It sounds trite and trivial to say, yet tell people you care, and value, and love them. Although no less than Pope Francis in a Christmas present to marriages under strain from the stress of the pandemic that the 3 key words to remember are please, sorry, and thank you.³ I am applying that sage advice liberally to all relationships and interactions in the daily grind of work and home. The cost is little, the reward priceless.

It is good and right to have high hopes. We all need to take care of ourselves, whether we make resolutions to do so or not. Though more than anything else what we need is to be kind to ourselves. It is presumptuous of me to tell you what wellness means for your individual struggle, as it is inhuman of me to deign to tell you to be resilient when many of you face intolerable working conditions.⁴ As Jackson Browne sang in “Rock Me on the Water”, “Everyone must have some thought that’s going to pull them through somehow. Find your own thought, the reason you keep getting up and going to care for patients who increasingly respond with the rage of denial and resentment. Amid what morally distressed public health professionals have called so many unnecessary deaths,choose what gives you reason to keep serving that other side of this life full of healing.⁵ And if like so many of my fellow health care professionals, you are so spent and bent, that you feel that you can no longer practice without becoming someone you do not want to be, then let go with grace, get the help you deserve and perhaps one day when rested and mended, find another way to give.⁶

I rarely self-disclose but I want to end this column with a personal story that exemplifies more than all these words living this simple message. My spouse is a health care practitioner at a Veterans Affairs medical center. Like all of you on the front lines they work far too long hours in difficult conditions, with challenging patients and not enough staff to care for them. My partner had not an hour to get any gifts for me or our furry children. On Christmas Eve, before a long shift, they went to a packed Walgreens to buy our huskies each a toy and me a pair of fuzzy slippers. We sat by the tree and opened the hastily wrapped packages, and nothing could have been more memorable or meaningful. All of us at Federal Practitioner wish you, our readers, find in 2022 many such moments to sustain you.

The new 2021 coronary revascularization guidelines are spurring controversy, as surgical associations raise concerns about the interpretation of the evidence behind key recommendations and the makeup of the writing committee.

The guideline was published in December by the American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI), and replaces the 2011 coronary artery bypass surgery (CABG) and the 2011 and 2015 percutaneous coronary intervention (PCI) guidelines.

The American Association for Thoracic Surgery (AATS) and Society of Thoracic Surgeons (STS) were part of the development of the document but have withdrawn their support, citing three areas of concern in a recent editorial in Annals of Thoracic Surgery.

“I do have to emphasize this is not just the AATS and STS – the European societies, Latin American societies, Asian societies, and even cardiologists are all coming out against these guidelines,” Joseph F. Sabik III, MD, University Hospitals Cleveland Medical Center, lead author of the editorial, said in an interview. “So, I think that tells us that something didn’t go right here.”

The main objection is the downgrading of CABG surgery from a class 1 to weak 2b recommendation to improve survival in patients with three-vessel coronary artery disease (CAD) and normal left ventricular function.

The ISCHEMIA trial was used to support this two-level downgrade and a class 1 to 2a downgrade for CABG in three-vessel CAD with mild to moderate left ventricular dysfunction. But the trial wasn’t powered for survival, only 20% of patients underwent CABG as the initial invasive strategy, and patients were followed for less than 5 years, the editorialists observed.

At the same time, there’s plenty of observational and randomized studies such as SYNTAX, EXCEL, and FAME 3 showing a clear survival benefit of CABG over PCI, Dr. Sabik said. “The criticism is that these are old studies and aren’t applicable today, but we don’t understand downgrading without any evidence suggesting it [CABG] isn’t effective anymore.”
 

CABG and PCI treated as equal

AATS and STS also object to the new guidelines treating PCI and CABG as equivalent revascularization strategies in decreasing ischemic events. Both were given a 2b recommendation for survival with triple-vessel disease, but randomized trials have demonstrated not only lower mortality with surgery but fewer reinterventions and myocardial infarctions.

“None of that gets acknowledged in the guidelines; they are treated equally,” Dr. Sabik said. “So if you’re going to say that CABG isn’t any better than medical therapy, in our mind, you have to say that PCI is worse than medical therapy. And we don’t believe that, I want you to know. We just think that the logic doesn’t make any sense. The committee used what it wanted to but didn’t use many things that committees have used in the past to give CABG a level 1 recommendation.”

The downgrade is also at odds with the 2018 European Society of Cardiology (ESC)/ European Association for Cardio-Thoracic Surgery (EACTS) guidelines, which give CABG a class 1 recommendation in three-vessel CAD as well as one- or two-vessel CAD with proximal left atrial descending artery stenosis.

In a Dec. 14 letter to the ACC/AHA Joint Committee, the Latin American Association of Cardiac and Endovascular Surgery (LACES) also called out the guideline committee for the 2b class of recommendation (COR) for PCI and CABG, saying it contradicts the text, which “clearly considers” the need to give a weaker endorsement for PCI than for CABG in patients with multivessel CAD.

“Considering that this section has the most significant impact due to the prevalence of stable ischemic heart disease in patients with multivessel CAD, such a contradiction may affect the lives and survival of millions of patients worldwide and have a major socioeconomic impact,” the letter states.

“Therefore, LACES respectfully but vehemently believes the Task Force should seriously reconsider the wording and recommendations in this specific large group of patients.”
 

Class I for radial conduit

AATS and STS also express concern about the new class 1 recommendation for the radial artery as a conduit in CABG. They note this is higher than bilateral internal mammary artery grafting and based on a meta-analysis of six relatively small studies with very strict inclusion criteria favorable for radial artery usage and patency.

“There’s a lot of studies that showed if you use the radial artery incorrectly, you have worse outcomes, and that’s what scares us a bit,” Dr. Sabik said. “If they’re giving it a class 1 recommendation, does that mean that becomes standard of care and could that cause patient harm? We think that level 1 is too high and that a [class] 2a with qualifications would be appropriate.”
 

Unequal footing

In a Dec. 23 letter, EACTS said it is “extremely concerned” about downgrading the COR for CABG without new randomized controlled trials to support the decision or to reject previously held evidence.

“The downgrading of CABG, and placing PCI at the same COR, does not meet our interpretation of the evidence, and may lead to avoidable loss of life,” EACTS officials said. “These guidelines also have implications on patient care: A COR IIb entails that CABG may not be reimbursable in some countries.”

EACTS called on AHA, ACC, and SCAI to review the evidence and called out the makeup of the guideline writing committee. “It is astonishing that no surgical association was involved, coauthored, or endorsed these guidelines.”

The AATS and STS each had a single representative on the guidelines’ writing committee but note that the six remaining surgeons were chosen by the ACC and AHA. Surgeons were also in the minority and only a majority was needed to approve the guidelines, highlighting the need to revisit the guideline development process to ensure equal representation by multidisciplinary experts across specialties.

“I hope the cardiology and surgical societies can come together and figure out how we do this better in the future, and we take a look again at these guidelines and come up with what we think is appropriate, especially since this is not just AATS and STS,” Dr. Sabik said.

In an emailed statement, the ACC/AHA said the AATS and STS representatives “actively participated throughout the writing process the past 3 years” and that the AATS and STS were involved in the “extensive peer review process” for the document with a reviewer from each organization. Nevertheless, AATS and STS both elected not to endorse the guidelines when at the organizational approval stage.

“Consequently, the AATS representative chose to stay with the committee and be recognized as having been appointed on behalf of the ACC and the AHA,” according to the statement. “The STS representative chose to withdraw from the committee and is not listed as a writing committee member on the final guideline. The final guideline reflects the latest evidence-based recommendations for coronary artery revascularization, as agreed by the ACC, AHA, SCAI, and the full writing committee.”

Despite pleas from the surgical groups to reconsider the evidence, “there is no further review process for the revascularization guideline,” the ACC/AHA spokesperson noted.

Jennifer S. Lawton, MD, chief of cardiac surgery at Johns Hopkins University, Baltimore, and guideline writing committee chair, did not respond to numerous requests for comment.

A version of this article first appeared on Medscape.com.

The new 2021 coronary revascularization guidelines are spurring controversy, as surgical associations raise concerns about the interpretation of the evidence behind key recommendations and the makeup of the writing committee.

The guideline was published in December by the American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI), and replaces the 2011 coronary artery bypass surgery (CABG) and the 2011 and 2015 percutaneous coronary intervention (PCI) guidelines.

The American Association for Thoracic Surgery (AATS) and Society of Thoracic Surgeons (STS) were part of the development of the document but have withdrawn their support, citing three areas of concern in a recent editorial in Annals of Thoracic Surgery.

“I do have to emphasize this is not just the AATS and STS – the European societies, Latin American societies, Asian societies, and even cardiologists are all coming out against these guidelines,” Joseph F. Sabik III, MD, University Hospitals Cleveland Medical Center, lead author of the editorial, said in an interview. “So, I think that tells us that something didn’t go right here.”

The main objection is the downgrading of CABG surgery from a class 1 to weak 2b recommendation to improve survival in patients with three-vessel coronary artery disease (CAD) and normal left ventricular function.

The ISCHEMIA trial was used to support this two-level downgrade and a class 1 to 2a downgrade for CABG in three-vessel CAD with mild to moderate left ventricular dysfunction. But the trial wasn’t powered for survival, only 20% of patients underwent CABG as the initial invasive strategy, and patients were followed for less than 5 years, the editorialists observed.

At the same time, there’s plenty of observational and randomized studies such as SYNTAX, EXCEL, and FAME 3 showing a clear survival benefit of CABG over PCI, Dr. Sabik said. “The criticism is that these are old studies and aren’t applicable today, but we don’t understand downgrading without any evidence suggesting it [CABG] isn’t effective anymore.”
 

CABG and PCI treated as equal

AATS and STS also object to the new guidelines treating PCI and CABG as equivalent revascularization strategies in decreasing ischemic events. Both were given a 2b recommendation for survival with triple-vessel disease, but randomized trials have demonstrated not only lower mortality with surgery but fewer reinterventions and myocardial infarctions.

“None of that gets acknowledged in the guidelines; they are treated equally,” Dr. Sabik said. “So if you’re going to say that CABG isn’t any better than medical therapy, in our mind, you have to say that PCI is worse than medical therapy. And we don’t believe that, I want you to know. We just think that the logic doesn’t make any sense. The committee used what it wanted to but didn’t use many things that committees have used in the past to give CABG a level 1 recommendation.”

The downgrade is also at odds with the 2018 European Society of Cardiology (ESC)/ European Association for Cardio-Thoracic Surgery (EACTS) guidelines, which give CABG a class 1 recommendation in three-vessel CAD as well as one- or two-vessel CAD with proximal left atrial descending artery stenosis.

In a Dec. 14 letter to the ACC/AHA Joint Committee, the Latin American Association of Cardiac and Endovascular Surgery (LACES) also called out the guideline committee for the 2b class of recommendation (COR) for PCI and CABG, saying it contradicts the text, which “clearly considers” the need to give a weaker endorsement for PCI than for CABG in patients with multivessel CAD.

“Considering that this section has the most significant impact due to the prevalence of stable ischemic heart disease in patients with multivessel CAD, such a contradiction may affect the lives and survival of millions of patients worldwide and have a major socioeconomic impact,” the letter states.

“Therefore, LACES respectfully but vehemently believes the Task Force should seriously reconsider the wording and recommendations in this specific large group of patients.”
 

Class I for radial conduit

AATS and STS also express concern about the new class 1 recommendation for the radial artery as a conduit in CABG. They note this is higher than bilateral internal mammary artery grafting and based on a meta-analysis of six relatively small studies with very strict inclusion criteria favorable for radial artery usage and patency.

“There’s a lot of studies that showed if you use the radial artery incorrectly, you have worse outcomes, and that’s what scares us a bit,” Dr. Sabik said. “If they’re giving it a class 1 recommendation, does that mean that becomes standard of care and could that cause patient harm? We think that level 1 is too high and that a [class] 2a with qualifications would be appropriate.”
 

Unequal footing

In a Dec. 23 letter, EACTS said it is “extremely concerned” about downgrading the COR for CABG without new randomized controlled trials to support the decision or to reject previously held evidence.

“The downgrading of CABG, and placing PCI at the same COR, does not meet our interpretation of the evidence, and may lead to avoidable loss of life,” EACTS officials said. “These guidelines also have implications on patient care: A COR IIb entails that CABG may not be reimbursable in some countries.”

EACTS called on AHA, ACC, and SCAI to review the evidence and called out the makeup of the guideline writing committee. “It is astonishing that no surgical association was involved, coauthored, or endorsed these guidelines.”

The AATS and STS each had a single representative on the guidelines’ writing committee but note that the six remaining surgeons were chosen by the ACC and AHA. Surgeons were also in the minority and only a majority was needed to approve the guidelines, highlighting the need to revisit the guideline development process to ensure equal representation by multidisciplinary experts across specialties.

“I hope the cardiology and surgical societies can come together and figure out how we do this better in the future, and we take a look again at these guidelines and come up with what we think is appropriate, especially since this is not just AATS and STS,” Dr. Sabik said.

In an emailed statement, the ACC/AHA said the AATS and STS representatives “actively participated throughout the writing process the past 3 years” and that the AATS and STS were involved in the “extensive peer review process” for the document with a reviewer from each organization. Nevertheless, AATS and STS both elected not to endorse the guidelines when at the organizational approval stage.

“Consequently, the AATS representative chose to stay with the committee and be recognized as having been appointed on behalf of the ACC and the AHA,” according to the statement. “The STS representative chose to withdraw from the committee and is not listed as a writing committee member on the final guideline. The final guideline reflects the latest evidence-based recommendations for coronary artery revascularization, as agreed by the ACC, AHA, SCAI, and the full writing committee.”

Despite pleas from the surgical groups to reconsider the evidence, “there is no further review process for the revascularization guideline,” the ACC/AHA spokesperson noted.

Jennifer S. Lawton, MD, chief of cardiac surgery at Johns Hopkins University, Baltimore, and guideline writing committee chair, did not respond to numerous requests for comment.

A version of this article first appeared on Medscape.com.

The new 2021 coronary revascularization guidelines are spurring controversy, as surgical associations raise concerns about the interpretation of the evidence behind key recommendations and the makeup of the writing committee.

The guideline was published in December by the American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI), and replaces the 2011 coronary artery bypass surgery (CABG) and the 2011 and 2015 percutaneous coronary intervention (PCI) guidelines.

The American Association for Thoracic Surgery (AATS) and Society of Thoracic Surgeons (STS) were part of the development of the document but have withdrawn their support, citing three areas of concern in a recent editorial in Annals of Thoracic Surgery.

“I do have to emphasize this is not just the AATS and STS – the European societies, Latin American societies, Asian societies, and even cardiologists are all coming out against these guidelines,” Joseph F. Sabik III, MD, University Hospitals Cleveland Medical Center, lead author of the editorial, said in an interview. “So, I think that tells us that something didn’t go right here.”

The main objection is the downgrading of CABG surgery from a class 1 to weak 2b recommendation to improve survival in patients with three-vessel coronary artery disease (CAD) and normal left ventricular function.

The ISCHEMIA trial was used to support this two-level downgrade and a class 1 to 2a downgrade for CABG in three-vessel CAD with mild to moderate left ventricular dysfunction. But the trial wasn’t powered for survival, only 20% of patients underwent CABG as the initial invasive strategy, and patients were followed for less than 5 years, the editorialists observed.

At the same time, there’s plenty of observational and randomized studies such as SYNTAX, EXCEL, and FAME 3 showing a clear survival benefit of CABG over PCI, Dr. Sabik said. “The criticism is that these are old studies and aren’t applicable today, but we don’t understand downgrading without any evidence suggesting it [CABG] isn’t effective anymore.”
 

CABG and PCI treated as equal

AATS and STS also object to the new guidelines treating PCI and CABG as equivalent revascularization strategies in decreasing ischemic events. Both were given a 2b recommendation for survival with triple-vessel disease, but randomized trials have demonstrated not only lower mortality with surgery but fewer reinterventions and myocardial infarctions.

“None of that gets acknowledged in the guidelines; they are treated equally,” Dr. Sabik said. “So if you’re going to say that CABG isn’t any better than medical therapy, in our mind, you have to say that PCI is worse than medical therapy. And we don’t believe that, I want you to know. We just think that the logic doesn’t make any sense. The committee used what it wanted to but didn’t use many things that committees have used in the past to give CABG a level 1 recommendation.”

The downgrade is also at odds with the 2018 European Society of Cardiology (ESC)/ European Association for Cardio-Thoracic Surgery (EACTS) guidelines, which give CABG a class 1 recommendation in three-vessel CAD as well as one- or two-vessel CAD with proximal left atrial descending artery stenosis.

In a Dec. 14 letter to the ACC/AHA Joint Committee, the Latin American Association of Cardiac and Endovascular Surgery (LACES) also called out the guideline committee for the 2b class of recommendation (COR) for PCI and CABG, saying it contradicts the text, which “clearly considers” the need to give a weaker endorsement for PCI than for CABG in patients with multivessel CAD.

“Considering that this section has the most significant impact due to the prevalence of stable ischemic heart disease in patients with multivessel CAD, such a contradiction may affect the lives and survival of millions of patients worldwide and have a major socioeconomic impact,” the letter states.

“Therefore, LACES respectfully but vehemently believes the Task Force should seriously reconsider the wording and recommendations in this specific large group of patients.”
 

Class I for radial conduit

AATS and STS also express concern about the new class 1 recommendation for the radial artery as a conduit in CABG. They note this is higher than bilateral internal mammary artery grafting and based on a meta-analysis of six relatively small studies with very strict inclusion criteria favorable for radial artery usage and patency.

“There’s a lot of studies that showed if you use the radial artery incorrectly, you have worse outcomes, and that’s what scares us a bit,” Dr. Sabik said. “If they’re giving it a class 1 recommendation, does that mean that becomes standard of care and could that cause patient harm? We think that level 1 is too high and that a [class] 2a with qualifications would be appropriate.”
 

Unequal footing

In a Dec. 23 letter, EACTS said it is “extremely concerned” about downgrading the COR for CABG without new randomized controlled trials to support the decision or to reject previously held evidence.

“The downgrading of CABG, and placing PCI at the same COR, does not meet our interpretation of the evidence, and may lead to avoidable loss of life,” EACTS officials said. “These guidelines also have implications on patient care: A COR IIb entails that CABG may not be reimbursable in some countries.”

EACTS called on AHA, ACC, and SCAI to review the evidence and called out the makeup of the guideline writing committee. “It is astonishing that no surgical association was involved, coauthored, or endorsed these guidelines.”

The AATS and STS each had a single representative on the guidelines’ writing committee but note that the six remaining surgeons were chosen by the ACC and AHA. Surgeons were also in the minority and only a majority was needed to approve the guidelines, highlighting the need to revisit the guideline development process to ensure equal representation by multidisciplinary experts across specialties.

“I hope the cardiology and surgical societies can come together and figure out how we do this better in the future, and we take a look again at these guidelines and come up with what we think is appropriate, especially since this is not just AATS and STS,” Dr. Sabik said.

In an emailed statement, the ACC/AHA said the AATS and STS representatives “actively participated throughout the writing process the past 3 years” and that the AATS and STS were involved in the “extensive peer review process” for the document with a reviewer from each organization. Nevertheless, AATS and STS both elected not to endorse the guidelines when at the organizational approval stage.

“Consequently, the AATS representative chose to stay with the committee and be recognized as having been appointed on behalf of the ACC and the AHA,” according to the statement. “The STS representative chose to withdraw from the committee and is not listed as a writing committee member on the final guideline. The final guideline reflects the latest evidence-based recommendations for coronary artery revascularization, as agreed by the ACC, AHA, SCAI, and the full writing committee.”

Despite pleas from the surgical groups to reconsider the evidence, “there is no further review process for the revascularization guideline,” the ACC/AHA spokesperson noted.

Jennifer S. Lawton, MD, chief of cardiac surgery at Johns Hopkins University, Baltimore, and guideline writing committee chair, did not respond to numerous requests for comment.

A version of this article first appeared on Medscape.com.

Even though men in midlife have more cardiovascular (CV) conditions and risk factors than women of the same age, women are more affected by these conditions in terms of cognitive decline, new research suggests.

Analyses of almost 1,400 participants in the population-based Mayo Clinic Study of Aging showed that diabetes, dyslipidemia, and coronary heart disease (CHD) all had stronger associations with global cognitive decline in women than in men.

“All men and women should be treated for cardiovascular risk factors and conditions, but this study really highlights the importance of very early and perhaps more aggressive treatment in women with these conditions,” co-investigator Michelle M. Mielke, PhD, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minn., told this news organization.

The findings were published online Jan. 5 in Neurology.
 

Assessing sex differences

Most previous studies in this area have focused on CV risk factors in midlife in relation to late-life dementia (after age 75) or on late-life vascular risk factors and late-life dementia, Dr. Mielke noted.

However, a few recent studies have suggested vascular risk factors can affect cognition even in midlife. The current investigators sought to determine whether there are sex differences in these associations.

They assessed 1,857 nondemented participants aged 50 to 69 years from the Mayo Clinic Study on Aging. The mean education level was 14.9 years, and the mean body mass index (BMI) was 29.7.

Among the participants, 78.9% had at least one CV condition or risk factor, and the proportion was higher in men than women (83.4% vs. 74.5%; P < .0001).

Frequency of each individual CV condition or risk factor was also higher in men than women, and they had more years of education and higher BMI but took fewer medications.

Every 15 months, participants had an in-person interview and physical examination that included a neurologic assessment and short test of memory.

The neuropsychological battery included nine tests across four domains: memory, language, executive function, and visuospatial skills. Researchers calculated z-scores for these domains and for global cognition.
 

Multiple cognitive domains

Whereas this study evaluated multiple cognitive domains, most previous research has focused on global cognitive decline and/or decline in only one or two cognitive domains, the investigators note.

They collected information from medical records on CV conditions such as CHD, arrhythmias, congestive heart failure, peripheral vascular disease (PVD), and stroke; and CV risk factors such as hypertension, diabetes, dyslipidemia, smoking status, and BMI.

Because of the small number of patients with stroke and PVD, these were classified as “other cardiovascular conditions” in the statistical analysis.

Researchers adjusted for sex, age, years of education, depressive symptoms, comorbidities, medications, and apolipoprotein E (APOE) genotyping. The mean follow-up was 3 years and did not differ by sex.

As some participants didn’t have a follow-up visit, the current analysis included 1,394 individuals. Those without follow-up visits were younger, had less education and more comorbidities, and took more medications compared with those with a follow-up.

Results showed most CV conditions were more strongly associated with cognitive function among women than men. For example, CHD was associated with global decline only in women (P < .05).

CHD, diabetes, and dyslipidemia were associated with language decline in women only (all, P < .05), but congestive heart failure was significantly associated with language decline in men only.

Dr. Mielke cautioned about reading too much into the language results for women.

“It’s an intriguing finding and definitely we need to follow up on it,” she said. However, “more studies are needed to examine sex differences before we start saying it only has an effect on language.”
 

‘Treat aggressively and right away’

The researchers were somewhat surprised by the study findings. Because there is a higher prevalence of CV conditions and risk factors in men, they presumed men would be more affected by these conditions, said Dr. Mielke.

“But that’s not what we saw; we saw the reverse. It was actually the women who were affected more by these cardiovascular risk factors and conditions,” she said.

As midlife is when women enter menopause, fluctuating estrogen levels may help explain the differential impact on cognition among women. But Dr. Mielke said she wants to “move beyond” just looking at hormones.

She pointed out there are a variety of psychosocial factors that may also contribute to an imbalance in the cognitive impact of CV conditions on women.

“Midlife is when many women are still taking care of their children at home, are also taking care of their adult parents, and may be undergoing more stress while continuing to do a job,” Dr. Miekle said.

Structural brain development and genetics may also contribute to the greater effect on cognition in women, the investigators note.

Dr. Mielke stressed that the current study only identifies associations. “The next steps are to understand what some of the underlying mechanisms for this are,” she said.

In the meantime, these new results suggest middle-aged women with high blood pressure, cholesterol, or glucose measures “should be treated aggressively and right away” said Dr. Mielke.

“For example, for women who are just starting to become hypertensive, clinicians should treat them right away and not watch and wait.”

Study limitations cited include that its sample was limited to Olmsted County, Minnesota – so results may not be generalized to other populations. Also, as researchers combined PVD and stroke into one group, larger sample sizes are needed, especially for stroke. Another limitation was the study did not have information on duration of all CV conditions or risk factors.
 

Helpful for tailoring interventions?

Commenting on the study, Glen R. Finney, MD, director, Memory and Cognition Program, Geisinger Health Clinic, Wilkes-Barre, Pennsylvania, said the results are important.

“The more we understand about risk factors for the development of Alzheimer’s disease and related dementias, the better we understand how we can reduce the risks,” said Dr. Finney, who was not involved with the research.

Awareness that CV conditions are major risk factors in midlife has been “definitely rising,” said Dr. Finney. “Many studies originally were looking at late life and are now looking more at earlier in the disease process, and I think that’s important.”

Understanding how sex, ethnicity, and other demographic variables affect risks can help to “tailor interventions” for individual patients, he said.

The study was supported by the National Institutes of Health, the GHR Foundation, and the Rochester Epidemiology Project. Dr. Mielke is a consultant for Biogen and Brain Protection Company and is on the editorial boards of Neurology and Alzheimer’s and Dementia. Dr. Finney has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Even though men in midlife have more cardiovascular (CV) conditions and risk factors than women of the same age, women are more affected by these conditions in terms of cognitive decline, new research suggests.

Analyses of almost 1,400 participants in the population-based Mayo Clinic Study of Aging showed that diabetes, dyslipidemia, and coronary heart disease (CHD) all had stronger associations with global cognitive decline in women than in men.

“All men and women should be treated for cardiovascular risk factors and conditions, but this study really highlights the importance of very early and perhaps more aggressive treatment in women with these conditions,” co-investigator Michelle M. Mielke, PhD, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minn., told this news organization.

The findings were published online Jan. 5 in Neurology.
 

Assessing sex differences

Most previous studies in this area have focused on CV risk factors in midlife in relation to late-life dementia (after age 75) or on late-life vascular risk factors and late-life dementia, Dr. Mielke noted.

However, a few recent studies have suggested vascular risk factors can affect cognition even in midlife. The current investigators sought to determine whether there are sex differences in these associations.

They assessed 1,857 nondemented participants aged 50 to 69 years from the Mayo Clinic Study on Aging. The mean education level was 14.9 years, and the mean body mass index (BMI) was 29.7.

Among the participants, 78.9% had at least one CV condition or risk factor, and the proportion was higher in men than women (83.4% vs. 74.5%; P < .0001).

Frequency of each individual CV condition or risk factor was also higher in men than women, and they had more years of education and higher BMI but took fewer medications.

Every 15 months, participants had an in-person interview and physical examination that included a neurologic assessment and short test of memory.

The neuropsychological battery included nine tests across four domains: memory, language, executive function, and visuospatial skills. Researchers calculated z-scores for these domains and for global cognition.
 

Multiple cognitive domains

Whereas this study evaluated multiple cognitive domains, most previous research has focused on global cognitive decline and/or decline in only one or two cognitive domains, the investigators note.

They collected information from medical records on CV conditions such as CHD, arrhythmias, congestive heart failure, peripheral vascular disease (PVD), and stroke; and CV risk factors such as hypertension, diabetes, dyslipidemia, smoking status, and BMI.

Because of the small number of patients with stroke and PVD, these were classified as “other cardiovascular conditions” in the statistical analysis.

Researchers adjusted for sex, age, years of education, depressive symptoms, comorbidities, medications, and apolipoprotein E (APOE) genotyping. The mean follow-up was 3 years and did not differ by sex.

As some participants didn’t have a follow-up visit, the current analysis included 1,394 individuals. Those without follow-up visits were younger, had less education and more comorbidities, and took more medications compared with those with a follow-up.

Results showed most CV conditions were more strongly associated with cognitive function among women than men. For example, CHD was associated with global decline only in women (P < .05).

CHD, diabetes, and dyslipidemia were associated with language decline in women only (all, P < .05), but congestive heart failure was significantly associated with language decline in men only.

Dr. Mielke cautioned about reading too much into the language results for women.

“It’s an intriguing finding and definitely we need to follow up on it,” she said. However, “more studies are needed to examine sex differences before we start saying it only has an effect on language.”
 

‘Treat aggressively and right away’

The researchers were somewhat surprised by the study findings. Because there is a higher prevalence of CV conditions and risk factors in men, they presumed men would be more affected by these conditions, said Dr. Mielke.

“But that’s not what we saw; we saw the reverse. It was actually the women who were affected more by these cardiovascular risk factors and conditions,” she said.

As midlife is when women enter menopause, fluctuating estrogen levels may help explain the differential impact on cognition among women. But Dr. Mielke said she wants to “move beyond” just looking at hormones.

She pointed out there are a variety of psychosocial factors that may also contribute to an imbalance in the cognitive impact of CV conditions on women.

“Midlife is when many women are still taking care of their children at home, are also taking care of their adult parents, and may be undergoing more stress while continuing to do a job,” Dr. Miekle said.

Structural brain development and genetics may also contribute to the greater effect on cognition in women, the investigators note.

Dr. Mielke stressed that the current study only identifies associations. “The next steps are to understand what some of the underlying mechanisms for this are,” she said.

In the meantime, these new results suggest middle-aged women with high blood pressure, cholesterol, or glucose measures “should be treated aggressively and right away” said Dr. Mielke.

“For example, for women who are just starting to become hypertensive, clinicians should treat them right away and not watch and wait.”

Study limitations cited include that its sample was limited to Olmsted County, Minnesota – so results may not be generalized to other populations. Also, as researchers combined PVD and stroke into one group, larger sample sizes are needed, especially for stroke. Another limitation was the study did not have information on duration of all CV conditions or risk factors.
 

Helpful for tailoring interventions?

Commenting on the study, Glen R. Finney, MD, director, Memory and Cognition Program, Geisinger Health Clinic, Wilkes-Barre, Pennsylvania, said the results are important.

“The more we understand about risk factors for the development of Alzheimer’s disease and related dementias, the better we understand how we can reduce the risks,” said Dr. Finney, who was not involved with the research.

Awareness that CV conditions are major risk factors in midlife has been “definitely rising,” said Dr. Finney. “Many studies originally were looking at late life and are now looking more at earlier in the disease process, and I think that’s important.”

Understanding how sex, ethnicity, and other demographic variables affect risks can help to “tailor interventions” for individual patients, he said.

The study was supported by the National Institutes of Health, the GHR Foundation, and the Rochester Epidemiology Project. Dr. Mielke is a consultant for Biogen and Brain Protection Company and is on the editorial boards of Neurology and Alzheimer’s and Dementia. Dr. Finney has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Even though men in midlife have more cardiovascular (CV) conditions and risk factors than women of the same age, women are more affected by these conditions in terms of cognitive decline, new research suggests.

Analyses of almost 1,400 participants in the population-based Mayo Clinic Study of Aging showed that diabetes, dyslipidemia, and coronary heart disease (CHD) all had stronger associations with global cognitive decline in women than in men.

“All men and women should be treated for cardiovascular risk factors and conditions, but this study really highlights the importance of very early and perhaps more aggressive treatment in women with these conditions,” co-investigator Michelle M. Mielke, PhD, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minn., told this news organization.

The findings were published online Jan. 5 in Neurology.
 

Assessing sex differences

Most previous studies in this area have focused on CV risk factors in midlife in relation to late-life dementia (after age 75) or on late-life vascular risk factors and late-life dementia, Dr. Mielke noted.

However, a few recent studies have suggested vascular risk factors can affect cognition even in midlife. The current investigators sought to determine whether there are sex differences in these associations.

They assessed 1,857 nondemented participants aged 50 to 69 years from the Mayo Clinic Study on Aging. The mean education level was 14.9 years, and the mean body mass index (BMI) was 29.7.

Among the participants, 78.9% had at least one CV condition or risk factor, and the proportion was higher in men than women (83.4% vs. 74.5%; P < .0001).

Frequency of each individual CV condition or risk factor was also higher in men than women, and they had more years of education and higher BMI but took fewer medications.

Every 15 months, participants had an in-person interview and physical examination that included a neurologic assessment and short test of memory.

The neuropsychological battery included nine tests across four domains: memory, language, executive function, and visuospatial skills. Researchers calculated z-scores for these domains and for global cognition.
 

Multiple cognitive domains

Whereas this study evaluated multiple cognitive domains, most previous research has focused on global cognitive decline and/or decline in only one or two cognitive domains, the investigators note.

They collected information from medical records on CV conditions such as CHD, arrhythmias, congestive heart failure, peripheral vascular disease (PVD), and stroke; and CV risk factors such as hypertension, diabetes, dyslipidemia, smoking status, and BMI.

Because of the small number of patients with stroke and PVD, these were classified as “other cardiovascular conditions” in the statistical analysis.

Researchers adjusted for sex, age, years of education, depressive symptoms, comorbidities, medications, and apolipoprotein E (APOE) genotyping. The mean follow-up was 3 years and did not differ by sex.

As some participants didn’t have a follow-up visit, the current analysis included 1,394 individuals. Those without follow-up visits were younger, had less education and more comorbidities, and took more medications compared with those with a follow-up.

Results showed most CV conditions were more strongly associated with cognitive function among women than men. For example, CHD was associated with global decline only in women (P < .05).

CHD, diabetes, and dyslipidemia were associated with language decline in women only (all, P < .05), but congestive heart failure was significantly associated with language decline in men only.

Dr. Mielke cautioned about reading too much into the language results for women.

“It’s an intriguing finding and definitely we need to follow up on it,” she said. However, “more studies are needed to examine sex differences before we start saying it only has an effect on language.”
 

‘Treat aggressively and right away’

The researchers were somewhat surprised by the study findings. Because there is a higher prevalence of CV conditions and risk factors in men, they presumed men would be more affected by these conditions, said Dr. Mielke.

“But that’s not what we saw; we saw the reverse. It was actually the women who were affected more by these cardiovascular risk factors and conditions,” she said.

As midlife is when women enter menopause, fluctuating estrogen levels may help explain the differential impact on cognition among women. But Dr. Mielke said she wants to “move beyond” just looking at hormones.

She pointed out there are a variety of psychosocial factors that may also contribute to an imbalance in the cognitive impact of CV conditions on women.

“Midlife is when many women are still taking care of their children at home, are also taking care of their adult parents, and may be undergoing more stress while continuing to do a job,” Dr. Miekle said.

Structural brain development and genetics may also contribute to the greater effect on cognition in women, the investigators note.

Dr. Mielke stressed that the current study only identifies associations. “The next steps are to understand what some of the underlying mechanisms for this are,” she said.

In the meantime, these new results suggest middle-aged women with high blood pressure, cholesterol, or glucose measures “should be treated aggressively and right away” said Dr. Mielke.

“For example, for women who are just starting to become hypertensive, clinicians should treat them right away and not watch and wait.”

Study limitations cited include that its sample was limited to Olmsted County, Minnesota – so results may not be generalized to other populations. Also, as researchers combined PVD and stroke into one group, larger sample sizes are needed, especially for stroke. Another limitation was the study did not have information on duration of all CV conditions or risk factors.
 

Helpful for tailoring interventions?

Commenting on the study, Glen R. Finney, MD, director, Memory and Cognition Program, Geisinger Health Clinic, Wilkes-Barre, Pennsylvania, said the results are important.

“The more we understand about risk factors for the development of Alzheimer’s disease and related dementias, the better we understand how we can reduce the risks,” said Dr. Finney, who was not involved with the research.

Awareness that CV conditions are major risk factors in midlife has been “definitely rising,” said Dr. Finney. “Many studies originally were looking at late life and are now looking more at earlier in the disease process, and I think that’s important.”

Understanding how sex, ethnicity, and other demographic variables affect risks can help to “tailor interventions” for individual patients, he said.

The study was supported by the National Institutes of Health, the GHR Foundation, and the Rochester Epidemiology Project. Dr. Mielke is a consultant for Biogen and Brain Protection Company and is on the editorial boards of Neurology and Alzheimer’s and Dementia. Dr. Finney has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.

The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.

“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.

The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”

However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
 

Ten trials, consistent cardiovascular benefits

Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.

The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).

Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).

Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.

On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.

All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
 

Benefits seen across age, sex, and race/ethnicity subgroups

While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).

By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).

And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.

“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.

The authors have no disclosures.

A version of this article first appeared on Medscape.com.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.

The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.

“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.

The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”

However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
 

Ten trials, consistent cardiovascular benefits

Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.

The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).

Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).

Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.

On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.

All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
 

Benefits seen across age, sex, and race/ethnicity subgroups

While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).

By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).

And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.

“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.

The authors have no disclosures.

A version of this article first appeared on Medscape.com.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.

The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.

“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.

The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”

However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
 

Ten trials, consistent cardiovascular benefits

Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.

The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).

Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).

Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.

On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.

All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
 

Benefits seen across age, sex, and race/ethnicity subgroups

While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).

By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).

And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.

“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.

The authors have no disclosures.

A version of this article first appeared on Medscape.com.

The antidepressant bupropion failed to improve sexual dysfunction in female cancer survivors, according to new findings published online in the Journal of Clinical Oncology.

Using the Female Sexual Function Index (FSFI) as a measurement tool, investigators found that desire scores were not significantly different for participants who received bupropion versus a placebo over the 9-week study period.

“Sexual health is a complex phenomenon and [our results suggest that] no one intervention is going to solve the broader issue,” lead author Debra Barton, RN, PhD, FAAN, professor in the School of Nursing at the University of Michigan, Ann Arbor, told this news organization.

Sexual dysfunction is common among cancer survivors and experienced across multiple cancer types and stages of disease. Research shows that as many as 70% of female cancer survivors report loss of desire, compared with up to one-third of the general population.

Common sexual concerns among female cancer survivors include low desire, arousal issues, lack of appropriate lubrication, difficulty in achieving orgasm, and pain with penetrative sexual activity. Additionally, these women may experience significant overlap of symptoms, and often encounter multiple sexual issues that are exacerbated by a range of cancer treatments.

“It’s a huge problem,” Maryam B. Lustberg, MD, MPH, from Yale Cancer Center, New Haven, Conn., and colleagues wrote in an accompanying editorial.

Despite the prevalence of sexual dysfunction among cancer survivors, effective treatments remain elusive. Preliminary evidence suggests that bupropion, already approved for seasonal affective disorder, major depressive disorder, and smoking cessation, may also enhance libido.

Dr. Barton and colleagues conducted this phase 2 trial to determine whether bupropion can improve sexual desire in female cancer survivors without undesirable side effects.

In the study, Dr. Barton and colleagues compared two dose levels of extended-release bupropion in a cohort of 230 postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (<3.3), who had completed definitive cancer therapy.

Participants were randomized to receive either 150 mg (79 patients) or 300 mg (74 patients) once daily of extended-release bupropion, or placebo (77 patients).

Barton and colleagues then evaluated whether sexual desire significantly improved over the 9-week study period comparing the bupropion arms and the placebo group.

Overall, the authors found no significant differences (mean between-arm change for 150 mg once daily and placebo of 0.02; P = .93; mean between-arm change for 300 mg once daily and placebo of –0.02; P = .92). Mean scores at 9 weeks on the desire subscale were 2.17, 2.27, and 2.30 for 150 mg, 300 mg, and the placebo group, respectively.

In addition, none of the subscales – which included arousal, lubrication, and orgasm – or the total score showed a significant difference between arms at either 5 or 9 weeks.

Bupropion did, however, appear to be well tolerated. No grade 4-5 treatment-related adverse events occurred. In the 150-mg bupropion arm, two patients (2.6%) experienced a grade 3 event (insomnia and headache) and one patient in the 300-mg bupropion arm (1.4%) and placebo arm (1.3%) experienced a grade 3 event related to treatment (hypertension and headache, respectively).

In the accompanying editorial, Dr. Lustberg and colleagues “applaud the authors for conducting a study in this population of cancer survivors,” noting that “evidenced-based approaches have not been extensively studied.”

Dr. Lustberg and colleagues also commented that other randomized controlled clinical trials evaluating sexual desire disorder assessed outcomes using additional metrics, such as the Female Sexual Distress Scale–Revised questionnaire, which measures distress related to sexual dysfunction and low desire, in particular.

“The use of specific validated instruments for libido in place of the FSFI might have helped determine the effect of the study intervention in this reported trial,” they wrote.

Overall, according to Dr. Lustberg and colleagues, the negative results of this study indicate that a multidisciplinary clinical approach may be needed.

“As much as we would like to have one intervention that addresses this prominent issue, the evidence strongly suggests that cancer-related sexual problems may need an integrative biopsychosocial model that intervenes on biologic, psychologic, interpersonal, and social-cultural factors, not just on one factor, such as libido,” they wrote. “Such work may require access to multidisciplinary care with specialists in women’s health, pelvic floor rehabilitation, and psychosocial oncology.”

Dr. Barton said she has been developing a multicomponent approach to addressing sexual health in female cancer survivors.

However, she noted, “there is still much we do not fully understand about the broader impact of the degree of hormone deprivation in the population of female cancer survivors. A better understanding would provide clearer targets for interventions.” 

The study was supported by the National Cancer Institute and Breast Cancer Research Foundation. Dr. Barton has disclosed research funding from Merck. Dr. Lustberg reported receiving honoraria from Novartis and Biotheranostics; consulting or advising with PledPharma, Disarm Therapeutics, Pfizer; and other relationships with Cynosure/Hologic.

A version of this article first appeared on Medscape.com.

The antidepressant bupropion failed to improve sexual dysfunction in female cancer survivors, according to new findings published online in the Journal of Clinical Oncology.

Using the Female Sexual Function Index (FSFI) as a measurement tool, investigators found that desire scores were not significantly different for participants who received bupropion versus a placebo over the 9-week study period.

“Sexual health is a complex phenomenon and [our results suggest that] no one intervention is going to solve the broader issue,” lead author Debra Barton, RN, PhD, FAAN, professor in the School of Nursing at the University of Michigan, Ann Arbor, told this news organization.

Sexual dysfunction is common among cancer survivors and experienced across multiple cancer types and stages of disease. Research shows that as many as 70% of female cancer survivors report loss of desire, compared with up to one-third of the general population.

Common sexual concerns among female cancer survivors include low desire, arousal issues, lack of appropriate lubrication, difficulty in achieving orgasm, and pain with penetrative sexual activity. Additionally, these women may experience significant overlap of symptoms, and often encounter multiple sexual issues that are exacerbated by a range of cancer treatments.

“It’s a huge problem,” Maryam B. Lustberg, MD, MPH, from Yale Cancer Center, New Haven, Conn., and colleagues wrote in an accompanying editorial.

Despite the prevalence of sexual dysfunction among cancer survivors, effective treatments remain elusive. Preliminary evidence suggests that bupropion, already approved for seasonal affective disorder, major depressive disorder, and smoking cessation, may also enhance libido.

Dr. Barton and colleagues conducted this phase 2 trial to determine whether bupropion can improve sexual desire in female cancer survivors without undesirable side effects.

In the study, Dr. Barton and colleagues compared two dose levels of extended-release bupropion in a cohort of 230 postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (<3.3), who had completed definitive cancer therapy.

Participants were randomized to receive either 150 mg (79 patients) or 300 mg (74 patients) once daily of extended-release bupropion, or placebo (77 patients).

Barton and colleagues then evaluated whether sexual desire significantly improved over the 9-week study period comparing the bupropion arms and the placebo group.

Overall, the authors found no significant differences (mean between-arm change for 150 mg once daily and placebo of 0.02; P = .93; mean between-arm change for 300 mg once daily and placebo of –0.02; P = .92). Mean scores at 9 weeks on the desire subscale were 2.17, 2.27, and 2.30 for 150 mg, 300 mg, and the placebo group, respectively.

In addition, none of the subscales – which included arousal, lubrication, and orgasm – or the total score showed a significant difference between arms at either 5 or 9 weeks.

Bupropion did, however, appear to be well tolerated. No grade 4-5 treatment-related adverse events occurred. In the 150-mg bupropion arm, two patients (2.6%) experienced a grade 3 event (insomnia and headache) and one patient in the 300-mg bupropion arm (1.4%) and placebo arm (1.3%) experienced a grade 3 event related to treatment (hypertension and headache, respectively).

In the accompanying editorial, Dr. Lustberg and colleagues “applaud the authors for conducting a study in this population of cancer survivors,” noting that “evidenced-based approaches have not been extensively studied.”

Dr. Lustberg and colleagues also commented that other randomized controlled clinical trials evaluating sexual desire disorder assessed outcomes using additional metrics, such as the Female Sexual Distress Scale–Revised questionnaire, which measures distress related to sexual dysfunction and low desire, in particular.

“The use of specific validated instruments for libido in place of the FSFI might have helped determine the effect of the study intervention in this reported trial,” they wrote.

Overall, according to Dr. Lustberg and colleagues, the negative results of this study indicate that a multidisciplinary clinical approach may be needed.

“As much as we would like to have one intervention that addresses this prominent issue, the evidence strongly suggests that cancer-related sexual problems may need an integrative biopsychosocial model that intervenes on biologic, psychologic, interpersonal, and social-cultural factors, not just on one factor, such as libido,” they wrote. “Such work may require access to multidisciplinary care with specialists in women’s health, pelvic floor rehabilitation, and psychosocial oncology.”

Dr. Barton said she has been developing a multicomponent approach to addressing sexual health in female cancer survivors.

However, she noted, “there is still much we do not fully understand about the broader impact of the degree of hormone deprivation in the population of female cancer survivors. A better understanding would provide clearer targets for interventions.” 

The study was supported by the National Cancer Institute and Breast Cancer Research Foundation. Dr. Barton has disclosed research funding from Merck. Dr. Lustberg reported receiving honoraria from Novartis and Biotheranostics; consulting or advising with PledPharma, Disarm Therapeutics, Pfizer; and other relationships with Cynosure/Hologic.

A version of this article first appeared on Medscape.com.

The antidepressant bupropion failed to improve sexual dysfunction in female cancer survivors, according to new findings published online in the Journal of Clinical Oncology.

Using the Female Sexual Function Index (FSFI) as a measurement tool, investigators found that desire scores were not significantly different for participants who received bupropion versus a placebo over the 9-week study period.

“Sexual health is a complex phenomenon and [our results suggest that] no one intervention is going to solve the broader issue,” lead author Debra Barton, RN, PhD, FAAN, professor in the School of Nursing at the University of Michigan, Ann Arbor, told this news organization.

Sexual dysfunction is common among cancer survivors and experienced across multiple cancer types and stages of disease. Research shows that as many as 70% of female cancer survivors report loss of desire, compared with up to one-third of the general population.

Common sexual concerns among female cancer survivors include low desire, arousal issues, lack of appropriate lubrication, difficulty in achieving orgasm, and pain with penetrative sexual activity. Additionally, these women may experience significant overlap of symptoms, and often encounter multiple sexual issues that are exacerbated by a range of cancer treatments.

“It’s a huge problem,” Maryam B. Lustberg, MD, MPH, from Yale Cancer Center, New Haven, Conn., and colleagues wrote in an accompanying editorial.

Despite the prevalence of sexual dysfunction among cancer survivors, effective treatments remain elusive. Preliminary evidence suggests that bupropion, already approved for seasonal affective disorder, major depressive disorder, and smoking cessation, may also enhance libido.

Dr. Barton and colleagues conducted this phase 2 trial to determine whether bupropion can improve sexual desire in female cancer survivors without undesirable side effects.

In the study, Dr. Barton and colleagues compared two dose levels of extended-release bupropion in a cohort of 230 postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (<3.3), who had completed definitive cancer therapy.

Participants were randomized to receive either 150 mg (79 patients) or 300 mg (74 patients) once daily of extended-release bupropion, or placebo (77 patients).

Barton and colleagues then evaluated whether sexual desire significantly improved over the 9-week study period comparing the bupropion arms and the placebo group.

Overall, the authors found no significant differences (mean between-arm change for 150 mg once daily and placebo of 0.02; P = .93; mean between-arm change for 300 mg once daily and placebo of –0.02; P = .92). Mean scores at 9 weeks on the desire subscale were 2.17, 2.27, and 2.30 for 150 mg, 300 mg, and the placebo group, respectively.

In addition, none of the subscales – which included arousal, lubrication, and orgasm – or the total score showed a significant difference between arms at either 5 or 9 weeks.

Bupropion did, however, appear to be well tolerated. No grade 4-5 treatment-related adverse events occurred. In the 150-mg bupropion arm, two patients (2.6%) experienced a grade 3 event (insomnia and headache) and one patient in the 300-mg bupropion arm (1.4%) and placebo arm (1.3%) experienced a grade 3 event related to treatment (hypertension and headache, respectively).

In the accompanying editorial, Dr. Lustberg and colleagues “applaud the authors for conducting a study in this population of cancer survivors,” noting that “evidenced-based approaches have not been extensively studied.”

Dr. Lustberg and colleagues also commented that other randomized controlled clinical trials evaluating sexual desire disorder assessed outcomes using additional metrics, such as the Female Sexual Distress Scale–Revised questionnaire, which measures distress related to sexual dysfunction and low desire, in particular.

“The use of specific validated instruments for libido in place of the FSFI might have helped determine the effect of the study intervention in this reported trial,” they wrote.

Overall, according to Dr. Lustberg and colleagues, the negative results of this study indicate that a multidisciplinary clinical approach may be needed.

“As much as we would like to have one intervention that addresses this prominent issue, the evidence strongly suggests that cancer-related sexual problems may need an integrative biopsychosocial model that intervenes on biologic, psychologic, interpersonal, and social-cultural factors, not just on one factor, such as libido,” they wrote. “Such work may require access to multidisciplinary care with specialists in women’s health, pelvic floor rehabilitation, and psychosocial oncology.”

Dr. Barton said she has been developing a multicomponent approach to addressing sexual health in female cancer survivors.

However, she noted, “there is still much we do not fully understand about the broader impact of the degree of hormone deprivation in the population of female cancer survivors. A better understanding would provide clearer targets for interventions.” 

The study was supported by the National Cancer Institute and Breast Cancer Research Foundation. Dr. Barton has disclosed research funding from Merck. Dr. Lustberg reported receiving honoraria from Novartis and Biotheranostics; consulting or advising with PledPharma, Disarm Therapeutics, Pfizer; and other relationships with Cynosure/Hologic.

A version of this article first appeared on Medscape.com.

Statins may be safe when used during pregnancy, with no increase in risk for fetal anomalies, although there may be a higher risk for low birth weight and preterm labor, results of a large study from Taiwan suggest.

The Food and Drug Administration relaxed its warning on statins in July 2021, removing the drug’s blanket contraindication in all pregnant women.

Removal of the broadly worded contraindication should “enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke,” the FDA said in their announcement.

“Our findings suggested that statins may be used during pregnancy with no increase in the rate of congenital anomalies,” wrote Jui-Chun Chang, MD, from Taichung Veterans General Hospital, Taiwan, and colleagues in the new study, published online Dec. 30, 2021, in JAMA Network Open.

“For pregnant women at low risk, statins should be used carefully after assessing the risks of low birth weight and preterm birth,” they said. “For women with dyslipidemia or high-risk cardiovascular disease, as well as those who use statins before conception, statins may be continuously used with no increased risks of neonatal adverse effects.”

The study included more than 1.4 million pregnant women aged 18 years and older who gave birth to their first child between 2004 and 2014.

A total of 469 women (mean age, 32.6 years; mean gestational age, 38.4 weeks) who used statins during pregnancy were compared with 4,690 matched controls who had no statin exposure during pregnancy.

After controlling for maternal comorbidities and age, women who used statins during pregnancy were more apt to have low-birth-weight babies weighing less than 2,500 g (risk ratio, 1.51; 95% confidence interval, 1.05-2.16) and to deliver preterm (RR, 1.99; 95% CI, 1.46-2.71).

The statin-exposed babies were also more likely to have a lower 1-minute Apgar score (RR, 1.83; 95% CI, 1.04-3.20). Importantly, however, there was no increase in risk for fetal anomalies in the statin-exposed infants, the researchers said.

In addition, for women who used statins for more than 3 months prior to pregnancy, maintaining statin use during pregnancy did not increase the risk for adverse neonatal outcomes, including congenital anomalies, low birth weight, preterm birth, very low birth weight, low Apgar scores, and fetal distress.

The researchers called for further studies to confirm their observations.

Funding for the study was provided by Taichung Veterans General Hospital. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Statins may be safe when used during pregnancy, with no increase in risk for fetal anomalies, although there may be a higher risk for low birth weight and preterm labor, results of a large study from Taiwan suggest.

The Food and Drug Administration relaxed its warning on statins in July 2021, removing the drug’s blanket contraindication in all pregnant women.

Removal of the broadly worded contraindication should “enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke,” the FDA said in their announcement.

“Our findings suggested that statins may be used during pregnancy with no increase in the rate of congenital anomalies,” wrote Jui-Chun Chang, MD, from Taichung Veterans General Hospital, Taiwan, and colleagues in the new study, published online Dec. 30, 2021, in JAMA Network Open.

“For pregnant women at low risk, statins should be used carefully after assessing the risks of low birth weight and preterm birth,” they said. “For women with dyslipidemia or high-risk cardiovascular disease, as well as those who use statins before conception, statins may be continuously used with no increased risks of neonatal adverse effects.”

The study included more than 1.4 million pregnant women aged 18 years and older who gave birth to their first child between 2004 and 2014.

A total of 469 women (mean age, 32.6 years; mean gestational age, 38.4 weeks) who used statins during pregnancy were compared with 4,690 matched controls who had no statin exposure during pregnancy.

After controlling for maternal comorbidities and age, women who used statins during pregnancy were more apt to have low-birth-weight babies weighing less than 2,500 g (risk ratio, 1.51; 95% confidence interval, 1.05-2.16) and to deliver preterm (RR, 1.99; 95% CI, 1.46-2.71).

The statin-exposed babies were also more likely to have a lower 1-minute Apgar score (RR, 1.83; 95% CI, 1.04-3.20). Importantly, however, there was no increase in risk for fetal anomalies in the statin-exposed infants, the researchers said.

In addition, for women who used statins for more than 3 months prior to pregnancy, maintaining statin use during pregnancy did not increase the risk for adverse neonatal outcomes, including congenital anomalies, low birth weight, preterm birth, very low birth weight, low Apgar scores, and fetal distress.

The researchers called for further studies to confirm their observations.

Funding for the study was provided by Taichung Veterans General Hospital. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Statins may be safe when used during pregnancy, with no increase in risk for fetal anomalies, although there may be a higher risk for low birth weight and preterm labor, results of a large study from Taiwan suggest.

The Food and Drug Administration relaxed its warning on statins in July 2021, removing the drug’s blanket contraindication in all pregnant women.

Removal of the broadly worded contraindication should “enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke,” the FDA said in their announcement.

“Our findings suggested that statins may be used during pregnancy with no increase in the rate of congenital anomalies,” wrote Jui-Chun Chang, MD, from Taichung Veterans General Hospital, Taiwan, and colleagues in the new study, published online Dec. 30, 2021, in JAMA Network Open.

“For pregnant women at low risk, statins should be used carefully after assessing the risks of low birth weight and preterm birth,” they said. “For women with dyslipidemia or high-risk cardiovascular disease, as well as those who use statins before conception, statins may be continuously used with no increased risks of neonatal adverse effects.”

The study included more than 1.4 million pregnant women aged 18 years and older who gave birth to their first child between 2004 and 2014.

A total of 469 women (mean age, 32.6 years; mean gestational age, 38.4 weeks) who used statins during pregnancy were compared with 4,690 matched controls who had no statin exposure during pregnancy.

After controlling for maternal comorbidities and age, women who used statins during pregnancy were more apt to have low-birth-weight babies weighing less than 2,500 g (risk ratio, 1.51; 95% confidence interval, 1.05-2.16) and to deliver preterm (RR, 1.99; 95% CI, 1.46-2.71).

The statin-exposed babies were also more likely to have a lower 1-minute Apgar score (RR, 1.83; 95% CI, 1.04-3.20). Importantly, however, there was no increase in risk for fetal anomalies in the statin-exposed infants, the researchers said.

In addition, for women who used statins for more than 3 months prior to pregnancy, maintaining statin use during pregnancy did not increase the risk for adverse neonatal outcomes, including congenital anomalies, low birth weight, preterm birth, very low birth weight, low Apgar scores, and fetal distress.

The researchers called for further studies to confirm their observations.

Funding for the study was provided by Taichung Veterans General Hospital. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A soon-to-be medical student and former oncology ward volunteer has received a $10,000 scholarship for her education recently after tipping off a Vancouver Canucks staff member about a cancerous mole on the back of his neck during a National Hockey League game in Seattle this past October.

Sitting immediately behind the visiting team’s bench, Nadia Popovici wrote a large-font message on her cell phone and tapped the protective glass to get the attention of Brian Hamilton, assistant equipment manager for the Canucks.

“The mole on the back of your neck is possibly cancerous. Please go see a doctor!” read the message.

Mr. Hamilton acted on the tip and was eventually diagnosed with a malignant stage II melanoma, according to a report in the Seattle Times.

As noted in a Medscape Q&A, “ABCDE” is the acronym that indicates the visible, physical characteristics suggestive of melanoma. ABCDE stands for asymmetry, irregular border, color variations (especially red, white, and blue tones in a brown or black lesion), diameter greater than 6 mm, and elevated surface. The lesions may itch, bleed, ulcerate, or develop satellites.

The Canucks returned to Seattle recently for another game against the Seattle Kraken, and the visiting team posted a note on social media from Mr. Hamilton seeking the identity of the good Samaritan.

“... the message you showed me on your cell phone will forever be etched into my brain and has made a true life-changing difference for me and my family,” wrote Mr. Hamilton.

Within hours, Ms. Popovici’s mother, whose family has season tickets to the Seattle team’s games, responded to the message.

Ms. Popovici and Mr. Hamilton met up again at the Jan. 1 game, where Ms. Popovici was rewarded with a $10,000 medical school scholarship in a surprise announcement, shared on Twitter and liked more than 42,000 times.

“She didn’t take me out of a burning car like the big stories, but she took me out of a slow fire. And the words out of the doctor’s mouth were, if I ignored that for 4-5 years, I wouldn’t be here,” Mr. Hamilton said at a news conference on Jan. 1.

Ms. Popovici says she has been accepted to several medical schools and will start school in the fall, according to a press release from the National Hockey League.

More money for medical school may be on the way for Ms. Popovici after a GoFundMe page was started. With a goal of $25,000, the fund had received just over $2,500 as of Jan. 4.

“The teams made a kind gesture of giving her 10K, but I think we can do better!” Josh Doxey, a sales manager from Lehi, Utah, wrote on the page he created for Ms. Popovici.

Mr. Doxey told this news organization, “I started the GoFundMe thinking it would be a nice gesture especially for someone going into health care after 2 crazy years of COVID ... I have gotten in touch with her and her mother, and have been chatting with both. They both seem incredibly kind, grateful, and humble.”

A version of this article first appeared on Medscape.com.

A soon-to-be medical student and former oncology ward volunteer has received a $10,000 scholarship for her education recently after tipping off a Vancouver Canucks staff member about a cancerous mole on the back of his neck during a National Hockey League game in Seattle this past October.

Sitting immediately behind the visiting team’s bench, Nadia Popovici wrote a large-font message on her cell phone and tapped the protective glass to get the attention of Brian Hamilton, assistant equipment manager for the Canucks.

“The mole on the back of your neck is possibly cancerous. Please go see a doctor!” read the message.

Mr. Hamilton acted on the tip and was eventually diagnosed with a malignant stage II melanoma, according to a report in the Seattle Times.

As noted in a Medscape Q&A, “ABCDE” is the acronym that indicates the visible, physical characteristics suggestive of melanoma. ABCDE stands for asymmetry, irregular border, color variations (especially red, white, and blue tones in a brown or black lesion), diameter greater than 6 mm, and elevated surface. The lesions may itch, bleed, ulcerate, or develop satellites.

The Canucks returned to Seattle recently for another game against the Seattle Kraken, and the visiting team posted a note on social media from Mr. Hamilton seeking the identity of the good Samaritan.

“... the message you showed me on your cell phone will forever be etched into my brain and has made a true life-changing difference for me and my family,” wrote Mr. Hamilton.

Within hours, Ms. Popovici’s mother, whose family has season tickets to the Seattle team’s games, responded to the message.

Ms. Popovici and Mr. Hamilton met up again at the Jan. 1 game, where Ms. Popovici was rewarded with a $10,000 medical school scholarship in a surprise announcement, shared on Twitter and liked more than 42,000 times.

“She didn’t take me out of a burning car like the big stories, but she took me out of a slow fire. And the words out of the doctor’s mouth were, if I ignored that for 4-5 years, I wouldn’t be here,” Mr. Hamilton said at a news conference on Jan. 1.

Ms. Popovici says she has been accepted to several medical schools and will start school in the fall, according to a press release from the National Hockey League.

More money for medical school may be on the way for Ms. Popovici after a GoFundMe page was started. With a goal of $25,000, the fund had received just over $2,500 as of Jan. 4.

“The teams made a kind gesture of giving her 10K, but I think we can do better!” Josh Doxey, a sales manager from Lehi, Utah, wrote on the page he created for Ms. Popovici.

Mr. Doxey told this news organization, “I started the GoFundMe thinking it would be a nice gesture especially for someone going into health care after 2 crazy years of COVID ... I have gotten in touch with her and her mother, and have been chatting with both. They both seem incredibly kind, grateful, and humble.”

A version of this article first appeared on Medscape.com.

A soon-to-be medical student and former oncology ward volunteer has received a $10,000 scholarship for her education recently after tipping off a Vancouver Canucks staff member about a cancerous mole on the back of his neck during a National Hockey League game in Seattle this past October.

Sitting immediately behind the visiting team’s bench, Nadia Popovici wrote a large-font message on her cell phone and tapped the protective glass to get the attention of Brian Hamilton, assistant equipment manager for the Canucks.

“The mole on the back of your neck is possibly cancerous. Please go see a doctor!” read the message.

Mr. Hamilton acted on the tip and was eventually diagnosed with a malignant stage II melanoma, according to a report in the Seattle Times.

As noted in a Medscape Q&A, “ABCDE” is the acronym that indicates the visible, physical characteristics suggestive of melanoma. ABCDE stands for asymmetry, irregular border, color variations (especially red, white, and blue tones in a brown or black lesion), diameter greater than 6 mm, and elevated surface. The lesions may itch, bleed, ulcerate, or develop satellites.

The Canucks returned to Seattle recently for another game against the Seattle Kraken, and the visiting team posted a note on social media from Mr. Hamilton seeking the identity of the good Samaritan.

“... the message you showed me on your cell phone will forever be etched into my brain and has made a true life-changing difference for me and my family,” wrote Mr. Hamilton.

Within hours, Ms. Popovici’s mother, whose family has season tickets to the Seattle team’s games, responded to the message.

Ms. Popovici and Mr. Hamilton met up again at the Jan. 1 game, where Ms. Popovici was rewarded with a $10,000 medical school scholarship in a surprise announcement, shared on Twitter and liked more than 42,000 times.

“She didn’t take me out of a burning car like the big stories, but she took me out of a slow fire. And the words out of the doctor’s mouth were, if I ignored that for 4-5 years, I wouldn’t be here,” Mr. Hamilton said at a news conference on Jan. 1.

Ms. Popovici says she has been accepted to several medical schools and will start school in the fall, according to a press release from the National Hockey League.

More money for medical school may be on the way for Ms. Popovici after a GoFundMe page was started. With a goal of $25,000, the fund had received just over $2,500 as of Jan. 4.

“The teams made a kind gesture of giving her 10K, but I think we can do better!” Josh Doxey, a sales manager from Lehi, Utah, wrote on the page he created for Ms. Popovici.

Mr. Doxey told this news organization, “I started the GoFundMe thinking it would be a nice gesture especially for someone going into health care after 2 crazy years of COVID ... I have gotten in touch with her and her mother, and have been chatting with both. They both seem incredibly kind, grateful, and humble.”

A version of this article first appeared on Medscape.com.

Adjunctive treatment with the novel oral medication REL-1017 (esmethadone) is effective in adults with major depressive disorder (MDD) who have failed other antidepressants, new research suggests.
 

REL-1017, from Relmada Therapeutics, is a novel N-methyl-D-aspartate receptor (NMDAR) channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission.

Jupiterimages/ThinkStock

Results from a phase 2a study showed rapid “therapeutic efficacy,” with a statistical difference by day 4, and the improvement was “robust,” with an effect size of 0.7 to 1. The positive outcome was also sustained for at least 1 week after treatment discontinuation, coinvestigator Paolo L. Manfredi, MD, chief scientific officer, Relmada Therapeutics, noted.

“Considering that the available traditional antidepressants have an average effect size around 0.3, this novel, potential rapid-acting antidepressant … holds great promise for millions of patients suffering from depression,” Dr. Manfredi told this news organization.

These results were obtained with a “very-well-tolerated once-daily oral NMDAR antagonist, without the dissociative effects seen with ketamine,” he added.

The findings were published online in the American Journal of Psychiatry.

‘Clear need’ for better therapies

It is estimated that more than half of patients with MDD fail to respond adequately following their first standard antidepressant treatment. In addition, responses are often delayed by 4-8 weeks after starting an antidepressant.

Therefore, there is a “clear need” to develop drugs for MDD that act quickly and with improved efficacy, the investigators note.

The phase 2a study of REL-1017 enrolled 62 adult patients (45% women) aged 18-65 years with moderate to severe MDD and no significant psychiatric comorbidity. All had failed to benefit from one to three standard antidepressant treatments in their current major depressive episode.

The researchers evaluated two doses of REL-1017 (25 mg and 50 mg once daily) vs. placebo given as adjunctive treatment. The assigned treatment lasted 7 days.

The primary study objectives were safety and tolerability. Results showed no serious adverse events (AEs), and no patients experienced treatment-emergent AEs that led to the stopping of treatment.

In addition, patients receiving the active drug experienced mild or moderate transient AEs comparable to placebo, with no opioid, dissociative, or psychotomimetic symptoms, or withdrawal effects when treatment ended.

The most common AEs reported were headache, constipation, nausea, and sleepiness.

Significant efficacy

The primary efficacy endpoint was the Montgomery–Åsberg Depression Scale (MADRS) score.

Mean MADRS score at baseline was 33.8 in the placebo group vs. 32.9 in the REL-1017 25-mg group and 35.2 in the REL-1017 50-mg group.

MADRS scores showed improvement on day 4 of treatment in both REL-1017 groups, and the improvement continued through day 7 (last dose) and day 14 (7 days after the last dose), with P ≤ .0308 and effect sizes ranging from 0.7 to 1.0.

Mean change from baseline in MADRS scores showed more improvement at the end of the dosing period for both dosing groups (–16.8 with 25 mg and –16.6 with 50 mg) vs. –8.8 with placebo.

Results of the other efficacy endpoints of Symptoms of Depression Questionnaire (SDQ) score and Clinical Global Impressions severity scale (CGI-S) and improvement scale (CGI-I) scores were similar to that of the MADRS.

Remission rates (defined as a MADRS score ≤10) on day 14, the last day of efficacy assessment, were 5% with placebo vs. 31% (P = .035) with REL-1017 25 mg and 39% (P = .01) with REL-1017 50 mg.

The number needed to treat to achieve remission on day 14 was four with the 25-mg dose and three with the 50-mg dose.

Phase 3 trials to confirm the efficacy and safety of REL-1017 are in progress, with topline results expected later this year, the investigators report.

The study was funded by Relmada Therapeutics. Dr. Manfredi has received personal fees from and/or held stock ownership in Relmada. Disclosures for the other investigators are fully listed in the original article.

A version of this article first appeared on Medscape.com.

Adjunctive treatment with the novel oral medication REL-1017 (esmethadone) is effective in adults with major depressive disorder (MDD) who have failed other antidepressants, new research suggests.
 

REL-1017, from Relmada Therapeutics, is a novel N-methyl-D-aspartate receptor (NMDAR) channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission.

Jupiterimages/ThinkStock

Results from a phase 2a study showed rapid “therapeutic efficacy,” with a statistical difference by day 4, and the improvement was “robust,” with an effect size of 0.7 to 1. The positive outcome was also sustained for at least 1 week after treatment discontinuation, coinvestigator Paolo L. Manfredi, MD, chief scientific officer, Relmada Therapeutics, noted.

“Considering that the available traditional antidepressants have an average effect size around 0.3, this novel, potential rapid-acting antidepressant … holds great promise for millions of patients suffering from depression,” Dr. Manfredi told this news organization.

These results were obtained with a “very-well-tolerated once-daily oral NMDAR antagonist, without the dissociative effects seen with ketamine,” he added.

The findings were published online in the American Journal of Psychiatry.

‘Clear need’ for better therapies

It is estimated that more than half of patients with MDD fail to respond adequately following their first standard antidepressant treatment. In addition, responses are often delayed by 4-8 weeks after starting an antidepressant.

Therefore, there is a “clear need” to develop drugs for MDD that act quickly and with improved efficacy, the investigators note.

The phase 2a study of REL-1017 enrolled 62 adult patients (45% women) aged 18-65 years with moderate to severe MDD and no significant psychiatric comorbidity. All had failed to benefit from one to three standard antidepressant treatments in their current major depressive episode.

The researchers evaluated two doses of REL-1017 (25 mg and 50 mg once daily) vs. placebo given as adjunctive treatment. The assigned treatment lasted 7 days.

The primary study objectives were safety and tolerability. Results showed no serious adverse events (AEs), and no patients experienced treatment-emergent AEs that led to the stopping of treatment.

In addition, patients receiving the active drug experienced mild or moderate transient AEs comparable to placebo, with no opioid, dissociative, or psychotomimetic symptoms, or withdrawal effects when treatment ended.

The most common AEs reported were headache, constipation, nausea, and sleepiness.

Significant efficacy

The primary efficacy endpoint was the Montgomery–Åsberg Depression Scale (MADRS) score.

Mean MADRS score at baseline was 33.8 in the placebo group vs. 32.9 in the REL-1017 25-mg group and 35.2 in the REL-1017 50-mg group.

MADRS scores showed improvement on day 4 of treatment in both REL-1017 groups, and the improvement continued through day 7 (last dose) and day 14 (7 days after the last dose), with P ≤ .0308 and effect sizes ranging from 0.7 to 1.0.

Mean change from baseline in MADRS scores showed more improvement at the end of the dosing period for both dosing groups (–16.8 with 25 mg and –16.6 with 50 mg) vs. –8.8 with placebo.

Results of the other efficacy endpoints of Symptoms of Depression Questionnaire (SDQ) score and Clinical Global Impressions severity scale (CGI-S) and improvement scale (CGI-I) scores were similar to that of the MADRS.

Remission rates (defined as a MADRS score ≤10) on day 14, the last day of efficacy assessment, were 5% with placebo vs. 31% (P = .035) with REL-1017 25 mg and 39% (P = .01) with REL-1017 50 mg.

The number needed to treat to achieve remission on day 14 was four with the 25-mg dose and three with the 50-mg dose.

Phase 3 trials to confirm the efficacy and safety of REL-1017 are in progress, with topline results expected later this year, the investigators report.

The study was funded by Relmada Therapeutics. Dr. Manfredi has received personal fees from and/or held stock ownership in Relmada. Disclosures for the other investigators are fully listed in the original article.

A version of this article first appeared on Medscape.com.

Adjunctive treatment with the novel oral medication REL-1017 (esmethadone) is effective in adults with major depressive disorder (MDD) who have failed other antidepressants, new research suggests.
 

REL-1017, from Relmada Therapeutics, is a novel N-methyl-D-aspartate receptor (NMDAR) channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission.

Jupiterimages/ThinkStock

Results from a phase 2a study showed rapid “therapeutic efficacy,” with a statistical difference by day 4, and the improvement was “robust,” with an effect size of 0.7 to 1. The positive outcome was also sustained for at least 1 week after treatment discontinuation, coinvestigator Paolo L. Manfredi, MD, chief scientific officer, Relmada Therapeutics, noted.

“Considering that the available traditional antidepressants have an average effect size around 0.3, this novel, potential rapid-acting antidepressant … holds great promise for millions of patients suffering from depression,” Dr. Manfredi told this news organization.

These results were obtained with a “very-well-tolerated once-daily oral NMDAR antagonist, without the dissociative effects seen with ketamine,” he added.

The findings were published online in the American Journal of Psychiatry.

‘Clear need’ for better therapies

It is estimated that more than half of patients with MDD fail to respond adequately following their first standard antidepressant treatment. In addition, responses are often delayed by 4-8 weeks after starting an antidepressant.

Therefore, there is a “clear need” to develop drugs for MDD that act quickly and with improved efficacy, the investigators note.

The phase 2a study of REL-1017 enrolled 62 adult patients (45% women) aged 18-65 years with moderate to severe MDD and no significant psychiatric comorbidity. All had failed to benefit from one to three standard antidepressant treatments in their current major depressive episode.

The researchers evaluated two doses of REL-1017 (25 mg and 50 mg once daily) vs. placebo given as adjunctive treatment. The assigned treatment lasted 7 days.

The primary study objectives were safety and tolerability. Results showed no serious adverse events (AEs), and no patients experienced treatment-emergent AEs that led to the stopping of treatment.

In addition, patients receiving the active drug experienced mild or moderate transient AEs comparable to placebo, with no opioid, dissociative, or psychotomimetic symptoms, or withdrawal effects when treatment ended.

The most common AEs reported were headache, constipation, nausea, and sleepiness.

Significant efficacy

The primary efficacy endpoint was the Montgomery–Åsberg Depression Scale (MADRS) score.

Mean MADRS score at baseline was 33.8 in the placebo group vs. 32.9 in the REL-1017 25-mg group and 35.2 in the REL-1017 50-mg group.

MADRS scores showed improvement on day 4 of treatment in both REL-1017 groups, and the improvement continued through day 7 (last dose) and day 14 (7 days after the last dose), with P ≤ .0308 and effect sizes ranging from 0.7 to 1.0.

Mean change from baseline in MADRS scores showed more improvement at the end of the dosing period for both dosing groups (–16.8 with 25 mg and –16.6 with 50 mg) vs. –8.8 with placebo.

Results of the other efficacy endpoints of Symptoms of Depression Questionnaire (SDQ) score and Clinical Global Impressions severity scale (CGI-S) and improvement scale (CGI-I) scores were similar to that of the MADRS.

Remission rates (defined as a MADRS score ≤10) on day 14, the last day of efficacy assessment, were 5% with placebo vs. 31% (P = .035) with REL-1017 25 mg and 39% (P = .01) with REL-1017 50 mg.

The number needed to treat to achieve remission on day 14 was four with the 25-mg dose and three with the 50-mg dose.

Phase 3 trials to confirm the efficacy and safety of REL-1017 are in progress, with topline results expected later this year, the investigators report.

The study was funded by Relmada Therapeutics. Dr. Manfredi has received personal fees from and/or held stock ownership in Relmada. Disclosures for the other investigators are fully listed in the original article.

A version of this article first appeared on Medscape.com.

The record-setting surge in COVID-19 cases nationwide – including more than one million new infections reported on Jan. 3 – raises questions about whether the higher Omicron variant transmissibility will accelerate a transition from pandemic to endemic disease.

Furthermore, does the steep increase in number of people testing positive for SARS-CoV-2 mean the United States could finally be achieving a meaningful level of “herd immunity”?

Infectious disease experts weigh in on these possibilities.
 

An endemic eventuality?

Whether the current surge will mean the predicted switch to endemic COVID-19 will come sooner “is very hard to predict,” Michael Lin, MD, MPH, told this news organization.

“It’s an open question,” he said, “if another highly transmissible variant will emerge.”

On a positive note, “at this point many more people have received their vaccinations or been infected. And over time, repeated infections have led to milder symptoms,” added Dr. Lin, hospital epidemiologist at Rush Medical College, Chicago.

“It could end up being a seasonal variant,” he said.

COVID-19 going endemic is “a real possibility, but unfortunately ... it doesn’t seem necessarily that we’re going to have the same predictable pattern we have with the flu,” said Eleftherios Mylonakis, MD, PhD, chief of infectious diseases for Lifespan and its affiliates at Rhode Island Hospital and Miriam Hospital in Providence.

“We have a number of other viruses that don’t follow the same annual pattern,” he said.  

Unknowns include how long individuals’ immune responses, including T-cell defenses, will last going forward.

A transition from pandemic to endemic is “not a light switch, and there are no metrics associated with what endemic means for COVID-19,” said Syra Madad, DHSc., MSc, MCP, an infectious disease epidemiologist at Harvard’s Belfer Center for Science and International Affairs, Boston.

“Instead, we should continue to focus on decreasing transmission rates and preventing our hospitals from getting overwhelmed,” she said.
 

A hastening to herd immunity?

“The short answer is yes,” Dr. Lin said when asked if the increased transmissibility and increased cases linked to the Omicron surge could get the U.S. closer to herd immunity.

“The twist in this whole story,” he said, “is the virus mutated enough to escape first-line immune defenses, specifically antibodies. That is why we are seeing breakthrough infections, even in highly vaccinated populations.”

Dr. Mylonakis was more skeptical regarding herd immunity.

“The concept of herd immunity with a rapidly evolving virus is very difficult” to address, he said.

One reason is the number of unknown factors, Dr. Mylonakis said. He predicted a clearer picture will emerge after the Omicrons surge subsides. Also, with so many people infected by the Omicron variant, immune protection should peak.

“People will have boosted immunity. Not everybody, unfortunately, because there are people who cannot really mount [a full immune response] because of age, because of immunosuppression, etc.,” said Dr. Mylonakis, who is also professor of infectious diseases at Brown University.

“But the majority of the population will be exposed and will mount some degree of immunity.”

Dr. Madad agreed. “The omicron variant will add much more immunity into our population by both the preferred pathway – which is through vaccination – as well as through those that are unvaccinated and get infected with omicron,” she said.

“The pathway to gain immunity from vaccination is the safest option, and already over 1 million doses of the COVID-19 vaccine are going into arms per day – this includes first, second, and additional doses like boosters,” added Dr. Madad, who is also senior director of the System-wide Special Pathogens Program at New York City Health and Hospitals.
 

A shorter, more intense surge?

The United Kingdom’s experience with COVID-19 has often served as a bellwether of what is likely to happen in the U.S. If that is the case with the Omicron surge, the peak should last about 4 weeks, Dr. Mylonakis said.

In other words, the accelerated spread of Omicron could mean this surge passes more quickly than Delta.

Furthermore, some evidence suggests neutralizing antibodies produced by Omicron infection remain effective against the Delta variant – thereby reducing the risk of Delta reinfections over time.

The ability to neutralize the Delta variant increased more than fourfold after a median 14 days, according to data from a preprint study posted Dec. 27 on MedRxiv.

At the same time, neutralization of the Omicron variant increased 14-fold as participants mounted an antibody response. The study was conducted in vaccinated and unvaccinated people infected by Omicron in South Africa shortly after symptoms started. It has yet to be peer reviewed.

Eric Topol, MD, editor-in-chief of Medscape, described the results as “especially good news” in a tweet.

The current surge could also mean enhanced protection in the future.

“As we look at getting to the other side of this Omicron wave, we will end up with more immunity,” Dr. Madad said. “And with more immunity means we’ll be better guarded against the next emerging variant.”

A version of this article first appeared on Medscape.com.

The record-setting surge in COVID-19 cases nationwide – including more than one million new infections reported on Jan. 3 – raises questions about whether the higher Omicron variant transmissibility will accelerate a transition from pandemic to endemic disease.

Furthermore, does the steep increase in number of people testing positive for SARS-CoV-2 mean the United States could finally be achieving a meaningful level of “herd immunity”?

Infectious disease experts weigh in on these possibilities.
 

An endemic eventuality?

Whether the current surge will mean the predicted switch to endemic COVID-19 will come sooner “is very hard to predict,” Michael Lin, MD, MPH, told this news organization.

“It’s an open question,” he said, “if another highly transmissible variant will emerge.”

On a positive note, “at this point many more people have received their vaccinations or been infected. And over time, repeated infections have led to milder symptoms,” added Dr. Lin, hospital epidemiologist at Rush Medical College, Chicago.

“It could end up being a seasonal variant,” he said.

COVID-19 going endemic is “a real possibility, but unfortunately ... it doesn’t seem necessarily that we’re going to have the same predictable pattern we have with the flu,” said Eleftherios Mylonakis, MD, PhD, chief of infectious diseases for Lifespan and its affiliates at Rhode Island Hospital and Miriam Hospital in Providence.

“We have a number of other viruses that don’t follow the same annual pattern,” he said.  

Unknowns include how long individuals’ immune responses, including T-cell defenses, will last going forward.

A transition from pandemic to endemic is “not a light switch, and there are no metrics associated with what endemic means for COVID-19,” said Syra Madad, DHSc., MSc, MCP, an infectious disease epidemiologist at Harvard’s Belfer Center for Science and International Affairs, Boston.

“Instead, we should continue to focus on decreasing transmission rates and preventing our hospitals from getting overwhelmed,” she said.
 

A hastening to herd immunity?

“The short answer is yes,” Dr. Lin said when asked if the increased transmissibility and increased cases linked to the Omicron surge could get the U.S. closer to herd immunity.

“The twist in this whole story,” he said, “is the virus mutated enough to escape first-line immune defenses, specifically antibodies. That is why we are seeing breakthrough infections, even in highly vaccinated populations.”

Dr. Mylonakis was more skeptical regarding herd immunity.

“The concept of herd immunity with a rapidly evolving virus is very difficult” to address, he said.

One reason is the number of unknown factors, Dr. Mylonakis said. He predicted a clearer picture will emerge after the Omicrons surge subsides. Also, with so many people infected by the Omicron variant, immune protection should peak.

“People will have boosted immunity. Not everybody, unfortunately, because there are people who cannot really mount [a full immune response] because of age, because of immunosuppression, etc.,” said Dr. Mylonakis, who is also professor of infectious diseases at Brown University.

“But the majority of the population will be exposed and will mount some degree of immunity.”

Dr. Madad agreed. “The omicron variant will add much more immunity into our population by both the preferred pathway – which is through vaccination – as well as through those that are unvaccinated and get infected with omicron,” she said.

“The pathway to gain immunity from vaccination is the safest option, and already over 1 million doses of the COVID-19 vaccine are going into arms per day – this includes first, second, and additional doses like boosters,” added Dr. Madad, who is also senior director of the System-wide Special Pathogens Program at New York City Health and Hospitals.
 

A shorter, more intense surge?

The United Kingdom’s experience with COVID-19 has often served as a bellwether of what is likely to happen in the U.S. If that is the case with the Omicron surge, the peak should last about 4 weeks, Dr. Mylonakis said.

In other words, the accelerated spread of Omicron could mean this surge passes more quickly than Delta.

Furthermore, some evidence suggests neutralizing antibodies produced by Omicron infection remain effective against the Delta variant – thereby reducing the risk of Delta reinfections over time.

The ability to neutralize the Delta variant increased more than fourfold after a median 14 days, according to data from a preprint study posted Dec. 27 on MedRxiv.

At the same time, neutralization of the Omicron variant increased 14-fold as participants mounted an antibody response. The study was conducted in vaccinated and unvaccinated people infected by Omicron in South Africa shortly after symptoms started. It has yet to be peer reviewed.

Eric Topol, MD, editor-in-chief of Medscape, described the results as “especially good news” in a tweet.

The current surge could also mean enhanced protection in the future.

“As we look at getting to the other side of this Omicron wave, we will end up with more immunity,” Dr. Madad said. “And with more immunity means we’ll be better guarded against the next emerging variant.”